Process for the production of 6alpha-fluoro-16alpha-halo pregnanes and the intermediates therefor



United States Patent 3,364,241 PROCESS FOR THE PRODUCTION OF 6a-FLUORO-IGa-HALO PREGNANES AND THE INTERMEDI- ATES THEREFOR John E. Pike andGeorge B. Spero, Kalamazoo, Mich.,

assignors to The Upjohn Company, Kalamazoo, Mich r a corporation ofDelaware No Drawing. Filed July 29, 1966, Ser. No. 568,778 7 Claims.(Cl. 260397.45)

This invention relates to a new chemical process and is moreparticularly concerned with an improvement in the production of6a-flI10l'0-16u-l1fll0 steroids of the pregnane series, wherein thehalogen is chlorine and fluorine, and with novel intermediates therefor.

Among the many anti-inflammatory steroids known,

those having both a 611- and 16u-halo substituent in a prednisolone-typestructure, are most desirable for reason of their high activities.

Thus, the anti-inflammatory activity (Granuloma pouch) can be tabulatedas follows:

Anti-inflammatory activity times hydrocortisone 104 Compound:

6m,16m-difiuoroprednisolone acetate 60,9a,16a-trifluoroprednisoneacetate 480 6u-fluoro-16a-chloroprednisolone acetate 5860:,9a-diflUOIO-1Gcz-ChIOIOPI'edIfiSOlOIIC acetate 1,100

ticular situation in which a 6cz-fll101'0 substituent is desired. In theabove cited US. Patents, it is necessary to treat a 2O(2l)-oxido-A-pregnene having a 6a-fiuoro substituent with hydrogen chloride orfluoride and subsequently with an acid anhydride to obtain 6a-fluoro-16halo-2l-hydroxy-l7(20)-pregnene as intermediate for the desirable finalproduct. In this reaction, considerable byproducts are obtained, and inaddition it involves a difficult and lengthy process to obtain thestarting 20(21)- oxido steroid. In the Belgian Patent 656,870, aFavorsky ester, i.e., an 1l-keto-17(20)-pregnen-2l-oic acid methyl 5ester is used, which must first be converted to a 16B-hydroxy analog andthen to a l6a-halo steroid. The thusobtained 16ahalo-11-keto-17(20)-pregnen-2l-oic acid methyl ester must then bereduced (ll-keto to llB-hydroxy-; 2l-carboxylic group to a 2l-alcoholicgroup) in the presence of 6- and 16-halogens. Lithium aluminum hydrideeliminates the l6oc-Cl1l01'0 substituent, but leaves a fia-fiuorosubstituent, diisobutyl aluminum hydride removes 6a-halo substituents,but leaves the 16a-chlorine atom attached. Similarly, other reducingreagents alfect the maintenance of the desired two halo substituents, inpositions 6 and 16. In addition it was observed that the introduction ofa 6-fiuorine atom with hydrogen fluoride into a 5u,6a-oxido steroid,after the chlorine was substituted in position 16 and the17-(acetyl-acetoxy)-side chain was established, proceeded in very lowyield. Consequently, the processes known up till now for the productionof 6a-fluoro-16u-halopregnane compounds were rather low in yield.

The present method avoids these low-yield steps and provides a novelmethod for the production of 60 160;-

"ice

halo pregnanes in good yield, which was hitherto not possible.

This novel method and the novel intermediates II and III can beillustratively represented as follows:

C 1120 Ac wherein R is selected from the group consisting of ketonicoxygen and a cyclic acetal of the formula in which R is an alkyleneradical containing up to 8 carbon atoms, inclusive, and the attachingoxygen to carbon bonds are separated by a chain of at least 2 and notmore than 3 carbon atoms; wherein R is selected from the groupconsisting of H\ H a" no and ketonic oxygen, wherein R is selected fromthe group consisting of hydrogen and fluorine; and wherein together Rand R can represent a -9(ll) double bond; wherein X is selected from thegroup consisting of chlorine and fluorine and wherein Ac is the acylradical of a hydrocar-bon carboxylic acid containing from 2 to 12 carbonatoms, inclusive.

The hydrocarbon carboxylic acids having from 2 to 12 carbon atoms,inclusive, herein referred to comprise I stituted alkanoic acids havingup to 12 carbon atoms, e.g.,

benzoic, phenylacetic, 2- and 3-phenylpropionic, phenylbutyric,phenylvaleric acids and the like; alicyclic acids, e.g., o.- andB-cyclopentylpropionic, cyclohexanemonocarboxylic acids; unsaturatedacids, such as acrylic, crotonic, 2-butynoic acid,chrysanthemummonocarboxylic' acid and the like.

comprises particularly the group in which R is ethylene, 1,3- and1,2-propylene; 1,2-butylene; 2,3-pentylene; 1,2- hexylene;1,2-heptylene; 1,2-octylene and the like.

The process of the present invention comprises: hydrolyzing with adilute aqueous mineral acid, e.g., perchloric acid, a5,6-oxido-16a-halo-17m,2l-dihydroxypregnan-ZO-one 21-acylate (I) toobtain the corresponding a,6,8,170c,21 tetrahydroxy16a-halopregnane-3,20- dione 21-acylate (II); treating II with afiuorinating agent having the Formula V.

wherein X is selected from the class consistingof chlorine and fluorine,X is selected from the class consisting of chlorine, fluorine andtrifluoromethyl, R and R" taken individually represent lower-alkyl, andR and R" taken together with the attached nitrogen atom represent theresidue of a heterocyclic radical containing from 5 to 7 ring atoms,inclusive, in an inert organic solvent to obtain the corresponding5m,17u,21-trihydroxy-6fifluoro-l6a-halopregnane-3,ZO-dione 21-acylate(III), and treating (III) with a mineral acid to obtain thecorresponding 60: fluoro 16a-hal0-l7a,2l-dihydroxy-4-pregnene-3,20-dione21-acylate (IV).

The term lower-alkyl means an alkyl radical containingfrom l to 8 carbonatoms, inclusive, such as methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl and isomeric forms thereof. The term heterocyclic radicalcontaining from 5 to 7 ring atoms, inclusive, is inclusive ofpyrrolidino, Z-methylpyrrolidino, 2,2-dimethylpyrrolidino, and. likealkylpyrrolidino groups, 4-methylpiperazino, 2,4-dimethylpiperazino, andlike alkylpiperazino groups, morpholino, piperidino, Z-methylpiperidino,3-methylpiperidino, and like alkylpiperidino groups, hexamethyleneimino,homomorpholino, and the like.

It will be obvious for the person skilled in the art that the productsof Formula IV can undergo further chemical reactions, e.g., treatmentwith selenium dioxide or fermentation with a microorganism such asCorynebacterium simplex, Septomyxa afiinis and others to establish a1,2-double bond; treatment with 2,3,5,6-tetrachloro-l,4-benzoquinone(chloranil) to introduce a 6,7- double bond; introduction of a9a-halogen into a 9a-hydrogen-llfi-hydroxy steroid by dehydration toobtain a 9(11)-double bond; converting such compound to thecorresponding halohydrin, e.g., with hyprobromous acid, then condensingthe halohydrin to the corresponding 9,6,11,6-oxido compound with a baseand finally treating with a hydrogen halide, e.g., hydrogen fluoride togive the corresponding 9a-fluoro-11fi-hydroxy steroid.

The object of this invention comprises not only the novel, improvedprocess, useful for the production of loa-chloroand16a-fiuoro-6u-fiuoropregnanes, but also the novel intermediates ofFormulae II and III; and in particular those useful for the productionof 604,9a-difluoro-l6a-chloroprednisolone acetate, namely, 511,601, 11,8,17a,21 pentahydroxy-l6u-chloropregnane-3,20-dione 21-acetate and5oc,1 15,17a,21-tetrahydroxy-6 3-fluoro-16m chloropregnane-3,ZO-dione21-acetate.

. The starting compounds for this process are either found in theliterature (Belgian Patent 656,870) or are prepared as shown in thepreparation.

In carrying out the process of the present invention, a selectedstarting material of Formula I, dissolved in an organic water-misciblesolvent, such as methanol, ethanol, acetone, dioxane, tetrahydrofuran,methyl ethyl ketone and the like, is treated with a. diluteaqueousmineral acid such as 5 to 10% aqueous sulfuric acid, hydrobromic acid,perchloric acid, hydrochloric acid, and the like, to give thecorresponding 5a,6p,17a,21-tetrahydroxy-16uhalopregnane-3,20-dione21-acylate. The reaction is generally carried out at room temperature,but may also be carried out at lower or higher temperatures. At roomtemperature, the reaction proceeds to completion during a period betweena /2 hour and 3 hours. After the reaction is completed, the product isobtained by concentrating the reaction mixture, thus removing a largepart of the organic solvent, and. adding water in which the newlyproduced product of Formula II is insoluble. The precipitate can becollected on filter and, if desired, may be purified byrecrystallization from acetone, ethyl acetate, Skellysolve B hexanes andmixtures thereof and the like.

The fluorination of the thus-obtained 50,6fi,17a,2l tetrahydroxy 16ahalopregnane-3,2O dione 2l-acylate (II) is carried out in an inertorganic solvent, that is, a solvent which cannot react with thefiuorinating agent. Such solvents comprise methylene chloride, benzene,toluene, chlorobenzene, pentane, hexane, cyclohexane, ethyl acetate,butyl acetate, acetone, methyl ethyl ketone, tetrahydrofuran, ethylether, chloroform, carbon tetrachloride, ethylene dichloride, ethylidenechloride, propylene chloride, trimethylene chloride, and the like, withmethylene chloride preferred.

Examples of the fluorinating agents having the Formula V are:

N-(Z-chloro-1,1,2-triflu0roethyl) diethylamine;

N-( 1,1,2,2-tetrafluoroethyl) diethylamine;N-(Z-chloro-1,1,2-trifluoroethyl)dimethylamine; N- (2-ch1oro-1, 1,2-trifluoroethyl )dipropylamine; N-(2-chloro-1,1,2-trifluoroethyl)diisobutylamine; N-(2-chloro-1, 1,2-trifiuoroethyl) dioctylamine;N-(2-chloro-l,1,2-trifluoroethyl)methylethylamine; N-(2,2-dichloro-1,l-difluoroethyl) diethylamine; N-( 1, 1,2,3 ,3,3-hexafiuoropropyl)diethylamine;

N-( l,1,2,2-tetrafluoroethyl) diisopropylamine,

and the like. The preferred fluorinating agent for use in the process ofthe invention is N-(2-chloro-1,1,2-trifluoroethyl) diethylamine.

Advantageously, but not necessarily, the process of the fiuorination. iscarried out in the presence of an acid catalyst such as a hydrogenhalide, phosphoric acid, sulfuric acid, boron trichloride, borontrifluoride, aluminum trifluoride, titanium tetrafluoride and preferablyhydrogen fluoride.

In the preferred embodiment of this invention, the fluorinating reagentis used in an excess such as from 2 to 6 times the molar equivalent for1 molar equivalent of steroid. The reaction is carried out generally atlow temperature between 0-10 C., however, lower or higher temperaturesare operative. It is further preferred that the steroid in solution isadded in portions over time intervals to the cooled solution of thefiuorinating agent and acid catalyst in the organic solvent. The timeintervals are selected according to the solubility of the steroid in thereaction mixture, that is, new steroid is only added when the prioraddition of steroid has completely gone into solution. When all steroidhas been reacted, the mixture is allowed to stir at low temperature foran additional period such as between 1 to 6 hours in order to producecompletion of the reaction. After the reaction is completed, the desiredproduct is recovered by conventional means such as destroying the acidcatalyst, for example, by adding a sodium bicarbonate solution,separating the water-immiscible phase, that is, the methylene chloridelayer in the preferred embodiment of this invention, washing thislayerand drying it, and obtaining theproduct by removal of the solventby evaporation.

The thus-obtained product, a 5u,l7a,21-trihydroxy-6 3-fluoro-l6a-halopregnane-3,ZO-dione 21-acetate, can be further purifiedby conventional means, e.g., chromatography or recrystallization fromorganic solvents such as acetone, methanol, Skellysolve B hexanemixtures thereof, and the like.

The dehydration step of the thus-obtained5tx,l7a,2ltrihydroxy-6fi-fiuoro-16a halopregnane-3,20-dione 21- acylate(III) is preferably carried out with an acid at low temperatures underwater-free conditions. For this purpose, the steroid is dissolved in awater-free organic solvent such as chloroform, carbon tetrachloride,dioxane or the like and treated with a gaseous hydrogen halide, e.g.,gaseous hydrogen chloride. The reaction is preferably carried out at lowtemperature, that is, between -30 and C. for between 1 and hours. Theproduct of the reaction is recovered by conventional means, usually byneutralizing the reaction solution through washing with a dilute basesuch as sodium bicarbonate and water, drying the solution andevaporating to dryness. The crude product can be purified inconventional manner such as recrystallization, chromatography or thelike. The products thus obtained are 6oz-fl110r0-16a-hal0-17cz,2l-dihydroxy-4-pregnene-3,ZO-dione 21-acylates (IV). Depending upontheir final purpose, these products can be, as mentioned before,converted to other steroids having halogens in positions 9, double bondsin position A and A or other important substituents particularly thellp-hydroxy group.

The following preparation and examples are illustrative of the processand products of this invention, but are not to be construed as limiting.

PREPARATION 1 50:,6cL-0Xld0-1 113,1 70:,21 -trihydr0xy-1 60cfluoro-pregnane- 3,20-dione S-ethylene cyclic acetal 21 -acetate Asolution was prepared containing 5 g. of 16a-fluorohydrocortisone21-acetate, 6 ml. of distilled ethylene glycol, 0.3 g. ofp-toluenesulfonic acid monohydrate and 125 ml. of benzene. This solutionwas refluxed under stirring for a period of 6 hours in a flask equippedwith a reflux condenser and a Water trap. The reaction mixture was thencooled, washed repeatedly with water and dilute sodium bicarbonatesolution and then dried and concentrated under reduced pressure todryness. The white crystalline residue obtained was11fl,17a,21-trihydroxy-16a-fluoro-5-pregnene-3,20-dione 3-ethylenecyclic acetal 2l-acetate.

To a solution of 5 g. of16wfluoro-11fi,17a,21-trihydroxy-5-pregnane-3,20-dione 3-ethylene cyclicacetal 21- acetate in 100 ml. of chloroform, was added a solution of 1.7g. of perbenzoic acid in 35 ml. of chloroform. The resulting solutionwas allowed to stand in a refrigerator at about 4 C. for a period of 24hours and thereupon at room temperature (about 25 C.) for an additionalperiod of 72 hours. The resulting reaction mixture was then washed with5% sodium bicarbonate solution and water, dried over anhydrous sodiumsulfate and evaporated to dryness to give a crude solid which was threetimes recrystallized from acetone to give 50:,6u-0Xid0-1lfi,17zz,21-trihydroxy-16a-fluoro-pregnane 3,20 dione 3-ethylene cyclicacetal 21-acetate.

In the same manner given in the preparation 16u-halo cortisone21-acylates, which can be substituted with other halogens or groups suchas with 9-fiu0ro, 9-bromo or 9- chloro, 12- or IS-methyl, or Reichsteinssubstance S 21- acylate can be converted to the corresponding 3-cyclicacetal-5a,6a-oxidosteroids which are useful for this process.

Example 1 .5a,6[3,115,1 70;,21 -pentahydroxy-J 6 achloro pregnane-3 ,2O-dr'one 21 acetate A suspension of g. of 5a,6x-oxido-1lfi,l7a,2l-trihydroxy-l6a-chloropregnane-3,20-dione 3-ethylenecyclic acetal ZI-acetate in 600 ml. of acetone and 50 ml. of 7%perchloric acid was stirred for 1.5 hours. The steroid dissolved duringa period of 5-10 minutes. The resulting solution was then diluted with200 ml. of Water and concentrated under reduced pressure at 60 C. untilthe acetone was removed. After the addition of 100 ml. of water andcooling for 2 hours in the refrigerator, the product was isolated byfiltration, washed well with water, and dried. A yield of 8.69 g. of5a,6,8,l1fi,17a,21-pentahydroxy-I6a-chloro-pregnane-3,20-dione2l-acetate was obtained, which after recrystallization from acetone hada melting point of 276277 C. (dec.).

Analysis.Calcd. for C H ClO C, 58.41; H, 7.03; Cl, 7.50. Found: C,58.42; H, 7.16; Cl, 7.53.

In the manner given in Example 1, 5a,6a,OXldO-1 1p,l7a,21-trihydroxy-l6a fluoropregnane 3,20 dione 3- ethylene cyclicacetal 21-acetate was hydrolyzed with 8% aqueous sulfuric acid for aperiod of minutes in acetone solution. The resulting reaction mixtureWas treated as before, that is, partially evaporated, diluted with waterand the product recovered by filtration. Recrystallization from acetonegave 5a,6fi,11,8,17a,21-pentahydroxy- 16e-fluoropregnane-3,20-dione21-acetate.

In the manner given in Example 1, other 5oc,6/3-17oz,21-tetrahydro-l6a-halopregnane-3,20-dione 2l-acylates can be produced byhydrolysis of5a,60c-OXld0-11B,17oc-dlhydroxy-l6a-halo-21-acyloxypregnane-3,20 dione21 acylates or the 3-alkylene ketals thereof. Representative compoundsthus produced include:5a,6B,11p,17a,21-pentahydroxy-9a,l6a-difiuoropregnane-3,20 dione21-acetate; 50,6B,11B,l7u,2l-pentahydroxy-9a-fluoro 16ozchloropregnane-3,20-dione ZI-acetate; 5a,6fi,17a,21tetrahydroxy-16a-chloropreguane-3,11,20-trione 21-acetate; 5a,6B,17a,21-tetrahydroxy-9a,l6or difluoropregnane 3,11, 20-trione21-acetate; 504,65,17m,21-tetrahyd.roxy-9(11)-dehydro-l6rx-chloropregnane-3,20-dione 21-acetate; 5a,6B,17a,21-tetrahydroxy-9(11)-dehydro-16a fluoropregnane-3,20-dione21-acetate and the like.

Example 3 .-5 (1,1 1fl,17v:,21-tetrahydroxy-6fi-fluoro-16alclzloro-pregnane-3,20-di0ne 21 -acetate A solution consisting of ml.of methylene chloride, 2 ml. ofN-(2chloro-1,1,2-trifluoroethyl)diethylamine and 0.25 ml. of 48%hydrofluoric acid was cooled to a temperature of 05 C. To this solutionwas added with stirring 1.5 g. of 5a,6B,11,8,17a,21-pentahydroxy-16achloropregnane-3,20-dione 21-acetate in portions of 0.5 g. The additionswere undertaken, each at 25 minute intervals, after the previousaddition had been completely gone into solution. The mixture was thenstirred at a temperature of between 05 C. for a total of 3.5 hours. Thehydrofluoric acid was destroyed by the addition of 100 ml. of saturatedsodium bicarbonate solution and the organic layer (methylene chloridelayer) was separated, washed with water, repeatedly, dried andchromatographed over g. of silica gel. The silica gel column was elutedwith 300 m1. fractions consisting of 30% ethyl acetate and 70%cyclohexane. Fractions 1 through 13 were discarded. Fractions 14 through26 were combined and evaporated to give 0.870 g. of product which wascrystallized from aectone-Skellysolve B hexanes to give 606 mg. of50,11,B,17a,2l-tetrahydroxy-rSfl-fiuoro- 16a-chloropregnane-3,20-dione2l-aceta'te of melting point 245246 C. (dec.).

Analysis.-Calcd. for C H ClFO C, 58.16; H, 6.79; CI, 7.47; F, 4.00.Found: C, 58.04; H, 6.77; Cl, 7.64; F, 3.98.

Example 4 .--5 01,] 1B,] 7a,.21 -tetrahydroxy-6fi,16a-difluor0-pregnane-3,20-dione 21 acetate In the manner given in Example 3,5a,6fi,11[:,17ot,21- pentahydroxy-l6rx-fluoropregnane-3,20-dione 21acetate was treated with N-(2-fluoro-l,1,2-trifluoroethyl)diethylamineto give 541,11B,17u,21-tetrahydroxy-6 3,16u-difiuoropregnane-3,20-dione21-acetate.

In the same manner as given in Example 3, other 5a,17tx,21 trihydroxy6,8 fluoro 16oz halopregnane- 3,20-dione 21-acylates are produced byreacting a selected a,6/3,17a,2l-tetrahydroxy16a-halopregnane-3,20-dione 2l-acylate with a reagent of Formula V suchas N-(2 chloro 1,1,2 trifiuoroethyl) diethylamine. Representativecompounds, thus obtained, include: 5a,l1;3,17a, 2l-tetrahydroxy65,911,160; trifluoropregnane-3,20-dione 21-acetate; 5a,11,8,17a,21tetrahydroxy 65,90: difluoro- 16a-chloropregnane-3,20-dione 2l-acetate;5u,17oz,21-tri hydroxy-Gfi-fluoro-l6u-chloropregnane-3,11,20-trione 21-acetate; 5a,17cc,21-trihydroxy 613,160: difluoropregnane- 3,11,20-trione2l-acetate;5a,17a,2l-trihydroxy-6fl,9a-difiuoro-l6a-chloropregnane-3,11,20-trione21-acetate; 50c, 17a,21-trihydroXy-6fi-fluoro-9(11)-dehydro-16a-chloropregnane-3,20-dione 21-acetate;5a,17a,2l-trihydroxy-6B, 16a-djfluoro-9(11)-dehydropregnane 3,20-dione21-acetate and the like.

Example 5.6a-flu0r0-16a-chlorohydrocortisone acetate A suspension of 1.0g. of 5a,11fi,17a,21-tetrahydroxy-6fi-fiuoro-16u-chlQropregnane-S,20-dione 21-acetate in 120 ml. ofchloroform and 0.8 ml. of absolute alcohol was cooled to 10 to C.Hydrogen chloride was bubbled through this mixture for 2 /2 hours whilethe temperature was maintained at -10 to --15 C. The reaction mixturewas then Washed with dilute sodium bicarbonate solution and severaltimes with water, dried over anhydrous sodium sulfate and evaporated todryness. The residue, thus obtained, was crystallized from acetone-Skell'ysolve B hexanes to give 642 mg. of6a-fl11OI'0-16occhlorohydrocortisone acetate which after additionalrecrystallization from acetone-Skellysolve B hexanes melted at 254 C. Asecond polymorphic form of 6a-fluoro-l6achlorohydrocortisone acetatemelted at 238240 C.

Anaiysis.-Calcd. for C H ClFO C, 60.45; H, 6.62; Cl, 7.76; F, 4.16.Found: C, 60.30; H, 6.86; CI, 8.11; F, 4.15.

Example 6.6a,161x-difluorohydrocortisone acetate In the manner given inExample 5, 5oz,11fi,17a,21-t6t1'ahydroxy-6B,16a-difluoropregnane 3,20dione Zl-acetate was treated with hydrogen chloride gas in methylenechloride solution containing a small amount of ethanol at a temperaturebetween and 10 C. to give 661,160- difluoro'hydrocortisone acetate.

In the manner given in Example 5, other dihalohydrocortisone andcortisone-type compounds of Formula 1V including ll-deoxy and9(11)-dehydro analogs can be obtained by treating the corresponding5a,17a,21-trihydroxy-6B-fluoro-16a-halopregnane-3,20-dione 21-acylateunder anhydrous conditions with hydrogen chloride or hydrogen bromidegas in an anhydrous medium. Representative compounds thus obtainedinclude: 6(1-fi1101'0- 16oc-chlOIOCOrtiS0ne acetate;6oc,16u-difll10I'OCOI'iSOH6 21- acetate; 6oz-fluO10-l6zx-Chl0r0 170:,21dihydroxy-4-pregnene-3,20-dione 2l-acetate; 6oz,16udifl11OI'0-17u,21dlhydroxy-4-pregnene-3,20-dione 21-acetate; 6afl11010-16achloro 17a,21dihydroxy 4,9(11) pregnadiene 3,20- dione 21 acetate; 60:,16a difluoro170;,21 dihydroxy- 4,9(11) pregnadiene 3,20 dione 21-acetate; 6a,9oc-difiuoro-l6a-chlorohydrocortis-one acetate; 6u,9oc,l6oc-'tl'ifiuorohydrocortisone acetate; 6u,9a-difiuoro-16a-chlorocortisoneacetate; 6a,9a,16a-tridiuorocortisone acetate and the like.

In the same manner given in the preceding examples, other acylates ofthe 'above 6a-fluoro-16a-halopregnanes can be produced by using astarting compound possessing an acyloxy group other than acetoxy. Inthis manner the propionates, butyrates, isobutyrates, valerates,isovalerates, hexanoates, heptanoates, octanoates, decanoates, laurates,benzoates, phenylacetates, phenylpropionates and the like of the above6a-fluoro-16a-halopregnanes are obtained.

Conversion of 6u-flu0ro-16a-chlorohydrocortisone acetate to6a-flu0r0-16a-chl0r0prednis0l0ne acetate A mixture of 600 mg. of6u-fluoro-la-chlorohydro cortisone acetate, 390 mg. of selenium dioxide,9 ml. of acetic acid and 42 ml. of t-butyl alcohol was stirred andrefluxed for 24 hours, the heat was then turned off and 0.6 g. ofmagnesium silicate was added. The mixture was stirred for 15 minutes andthen filtered, and the filtrate concentrated to give a residue.Purification of the residue gave 6a-fluoro-l6a-chloroprednisoloneacetate of melting point 29029l C.

Analysis.C-alcd. for C H CIFO C, 60.72; H, 6.20; Cl, 7.79; F, 4.18.Found: C, 60.62; H, 6.64; Cl, 7.61; F, 4.01.

A solution of 592 mg. of 6oc-flHOI'0-16a-Chl0f0- prednisolone acetatewas first treated with 284 mg. of N-bromoacetamide in 8.5 mg. ofpyridine for a period of 20 minutes at a temperature of 51 0 C.Thereupon, a stream of sulfur dioxide was passed over the surface of thesolution while stirring at a rate as to maintain a temperature below 15C. After the sulfur dioxide addition was complete (1520 minutes), waterwas added and the product obtained by extraction with ether and ethylacetate. After recrystallization from acetone-Skellysolve B hexanes,6a-fluoro 16oz chloro 17a,21 dihydroxy-1,4,9(11)-pregnatriene-3,20-dione 21-acetate of melting point 187-189 C. wasobtained. Recrystallization of this material raised the melting point to191193 C.

An'alysis.Calcd. for C H ClFO C, 63.22; H, 6.00; Cl, 8.12; F, 4.35.Found: C, 63.51; H, 6.24; Cl, 7.95; F, 4.24.

To a solution of 1.25 g. of 6a-fluoro-16a-chloro-17-oc,21- dihydroxy1,4,9(11) pregnatriene-3,20-dione 2l-acetate and 19.2 ml. of tertiarybutyl alcohol was added under stirring 2.8 m1. of 70% perchloric acid in22 m1. of water; then was added 520 mg. of N-bromoacetamide in 9 ml. oftertiary butyl alcohol. Afteer stirring for 15 minutes, the reactionmixture was diluted with a solution of 520 mg. of sodium sulfite in 29ml. of water and then concentrated under reduced pressure at 60 C. togive a slurry which was cooled, filtered and the resulting precipitatewashed with water and dried. The thus-obtained 6a-fluoro-9'on-bI'OmO-ll/3,17oc,2l trihydroxy 16achloro-1,4-pregnadiene-3,20-dione 21-acetate was obtained in a yield of1.48 g. having a melting point of 227230 C. (dec.).

This total material, 1.48 g., of above was dissolved in ml. of acetone,sodium acetate was added (1.48 g.) and the mixture was allowed to stirand reflux for 17 hours. The reaction mixture was then concentratedunder reduced pressure and the resulting crude product was purified bychromatography and recrystallization from acetone-Skellysolve B hexanesto give 975 mg. of 6a-fluoro 93,1 lB-oxidod6a-chloro-17a,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acetate ofmelting point 210- 212 C.

Analysis.Calcd. for C H ClFO C, 60.99; H, 5.79; CI, 7.83; F, 4.20.Found: C, 61.07; H, 6.07; Cl, 7.81; F. 4.12.

To 7.28 g. of hydrogen fluoride, cooled in a Dry Iceethanol bath, wasadded 8.85 ml. of precooled tetrahydrofurau followed by a precooledsolution of 783 mg. of 6afluoro 919,116oxido-16a-chloro-17a,21-dihydroxy-l,4- pregnadiene-3,20-dione 21-acetatein 22.4 ml. of methyl-' ene chloride. The resulting mixture was allowedto stand at 5 C. for 23 hours, was then carefully poured into 200 ml. ofcrushed ice and water containing 30 g. of sodium bicarbonate. Theorganic layer was separated and worked up to give 825 mg. of crudematerial, which after recrystallization from acetone gave 510 mg. of6u,9czdlfi1101O 16a-chloroprednisolone acetate having a melting point of303 C. (dec.) after additional recrystallization from acetone.

9 We claim: 1. A process for the production of aGm-fillOI'O-lfiuthalo-4-pregnene-3,20-dione acylate of the Formula IV:

IV wherein R is selected from the group consisting of CHzOAc wherein Ris selected from the group consisting of ketonic oxygen and a cyclicacetal of the formula in which R is an alkylene radical containing up to8 carbon atoms, inclusive, and the attaching oxygen to carbon bonds areseparated by a chain of at least 2 and not more than 3 carbon atoms; andwherein R R X and Ac are defined as hereinabove; to obtain thecorresponding 50:,

6B,17a,2l-tetrahydroXypregnane-3,20-di0ne 21-acylate of Formula II:

wherein R R X and Ac are defined as hereinabove; treating Compound IIwith a fluorinating agent of the Formula V:

wherein X is selected from the class consisting of chlorine andfluorine, X is selected from the class consisting of chlorine, fluorineand trifluoromethyl, R and R" taken individually represent lower-alkyl,R and 'R" taken together with the attached nitrogen atom represent theresidue of a heterocyclic radical containing from 5 to 7 ring atoms,inclusive, to obtain the corresponding 5a,l7oc,2ltrihydroxyB-fluoro-l6a-halopregnane-3,20-dione 2 l-acylate of Formula III:

with a fluorinating agent of the formula:

R F H X1 \HL R5 1! \X2 wherein X; is selected from the class consistingof chlorine and fluorine, X is selected from the class consisting ofchlorine, fluorine and trifluoromethyl, R and R taken individuallyrepresent loWer-alkyl, R and R taken together with the attached nitrogenatom represent the residue of a heterocyclic radical containing from 5to 7 ring atoms, inclusive, to obtain the corresponding 5a,11/8, 17a,21tetrahydroxy 65 fluoro 16oz chloropregnane- 3,20-dione 21-acetate anddehydrating this compound with an anhydrous mineral acid to obtain6a-fluoro-l6txchlorohydrocortisone 21-acetate.

3. The process of claim 2, wherein the dilute aqueous mineral acid forthe hydrolysis is dilute aqueous perchloric acid, the fluorinating agentis N-(2-chloro-l,1,2- trifluoroethyl)diethylamine, and the dehydrationis carried out with hydrogen chloride gas.

4. A 5a,6,B,17a,21-tetrahydroxypregnane-3,20-dione 21- acylate ofFormula II:

and ketonic oxygen, wherein R is selected from the group consisting ofhydrogen and fluorine; and wherein together R and R; can represent a9(11)-double bond; wherein X is selected from the group consisting offluorine and chlorine and wherein Ac is the acyl radical of a hywhereinR is selected from the group consisting of and ketonic oxygen; wherein Ris selected from the group consisting of hydrogen and fluorine; andwherein together R and R can represent a 9(11)-double bond, wherein X isselected from the group consisting of fluorine and chlorine and whereinAc is the acyl radical of a hydrocarbon carboxylic acid containing from2 to 12 carbon atoms, inclusive.

'7. 5a,11|3,17u,21 tetrahydroxy 6B fluoro-16u-chloropregnane-3,20-dioneZI-acetate.

References Cited UNITED STATES PATENTS 3,305,546 2/1967 Pike 260239.55

E. L. ROBERTS, Primary Examiner.

4. A 5A,6B,17A,21-TETRAHYDROXYPREGNANE-3,20-DIONE 21ACYLATE OF FORMULAII: